| 80% |
With sodium hydroxide In water at 20 - 75℃; |
Ae
After dissolution of 16.0 g of compound 17 (1.0 eq.) in 2.56 L of EtOH and 0.64 L of H2O by heating, followed by filtration, 39 mL of 1 N NaOHaq.(1.0 eq.) was added to the solution at 75 0C. The solution was gradually cooled to room temperature. Filtration, washing with80 mL of EtOH and drying provided 13.5 g of compound 18 (80% yield) as a crystal.1H NMR(300 MHz, DMSO-CZ6) δ 10.73 (t, J = 6.0 Hz, 1 H), 7.89 (s, 1 H), 7.40-7.30 (m, 1 H),7.25-7.16 (m, 1 H), 7.07-6.98 (m, 1 H), 5.21 (dd, J = 3.8, 10.0 Hz, 1 H), 4.58 (dd, J = 3.8, 12.1 Hz, 1H), 4.51 (d, J = 5.4 Hz, 2H), 4.30-4.20 (m, 2H), 3.75 (dd, J = 10.0, 12.1 Hz1 1H),3.65-3.55 (m, 1 H), 1.27 (d, J = 6.1 Hz, 3H). |
| 80% |
With sodium hydroxide In ethanol; water at 75℃; Heating; |
1.l Preparation 1(3S, 11 aR)-N-[(2,4-Difluorophenyl)methyl] -6-hy-droxy-3-methyl-5,7-dioxo-2,3,5,7, 11,1 la-hexahydro[1 ,3]oxazolo[3,2-a]pyrido[ 1 ,2-d]pyrazine-8-carboxa-mide sodium salt (compound lb, scheme 2)
Preparation 1(3S, 11 aR)-N-[(2,4-Difluorophenyl)methyl] -6-hy-droxy-3-methyl-5,7-dioxo-2,3,5,7, 11,1 la-hexahydro[1 ,3]oxazolo[3,2-a]pyrido[ 1 ,2-d]pyrazine-8-carboxa-mide sodium salt (compound lb, scheme 2) 1) Synthesis of (3S,l laR)-N-[(2,4-difluorophenyl)me-thyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,ll,l la-hexahydro[ 1 ,3]oxazolo[3,2-a]pyrido[ 1 ,2-d]pyrazine-8- carboxamide sodium salt (compound lb). After dissolution of 16.0 g of compound la (1.0 eq.) in 2.56 E of EtOH and 0.64 E of H20 by heating, followed byfiltration, 39 mE of 1 N NaOHaq. (1.0 eq.) was added tothe solution at 75° C. The solution was gradually cooledto room temperature. Filtration, washing with 80 mE of EtOH and drying provided 13.5 g of compound lb (80% yield) as a solid. ‘H NMR (300 MHz, DMSO-d5) ö10.73 (t, J=6.0 Hz, 1H), 7.89 (s, 1H), 7.40-7.30 (m, 1H),7.25-7.16 (m, 1H), 7.07-6.98 (m, 1H), 5.21 (dd, J=3.8,10.0 Hz, 1H), 4.58 (dd, J=3.8, 12.1 Hz, 1H), 4.51 (d, J=5.4 Hz, 2H), 4.30-4.20 (m, 2H), 3.75 (dd, J=l0.0, 12.1 Hz, 1H), 3.65-3.55 (m, 1H), 1.27 (d, J=6.l Hz, 3H). |
| 80% |
With sodium hydroxide In ethanol; water at 75℃; |
Ae
After dissolution of 16.0 g of compound 17 (1.0 eq.) in 2.56 L of EtOH and 0.64 L of H2O by heating, followed by filtration, 39 mL of 1N NaOHaq. (1.0 eq.) was added to the solution at 75° C. The solution was gradually cooled to room temperature. Filtration, washing with 80 mL of EtOH and drying provided 13.5 g of compound 18 (80% yield) asacrystal. |
| 79% |
With sodium hydroxide In methanol; water at 58 - 60℃; for 1h; |
17 Example 17: Preparation of sodium salt of compound (lb) (n =1)
Example 17: Preparation of sodium salt of compound (lb) (n =1) The compound (lb) (2 g, 0.049moles) was dissolved in methanol (20 ml) at 58- 60°C. To the reaction mixture was added 2N aqueous NaOH solution (2.5 ml) and stirred further for 1 hour. The reaction mixture was cooled to room temperature and stirred for 1 hour. The solid was isolated by filtration, washed with methanol and dried to afford 1.68 g of titled compound. Efficiency: 79 % |
| 5 g |
With sodium hydroxide In ethanol at 70 - 75℃; for 0.5h; |
9 Example 9: Preparation of Form N-II of (3S,llaR)-N-[(2,4- difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 11a- hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8-carboxamide , sodium salt
Compound (3S, 1 laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7- dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2-a]pyrido[l, 2-d]pyrazine-8- carboxamide (5 g, 0.01234 moles ) stirred in a mixture of ethanol (800 ml) and water ( 200 ml) at room temperature. The suspension was heated under stirring to 70-75°C and treated with IN sodium hydroxide solution (12.5 ml). The resulting suspension was heated under stirring to 70-75°C, for 30 minutes, cooled to room temperature and further stirred for about 1 hour. The solid was isolated by filtration and dried under vacuum at 50°C -55°C for 12-15 hours to yield 5.0 g of titled compound. The XRD of the final product is set forth in FIG. 6 and was recorded and identified as polymorph Form N-II of(3S, l laR)-N-[(2,4-difluorophenyl)methyl]-6- hydroxy-3-methyl-5, 7-dioxo-2, 3,5,7, 11, 1 la-hexahydro[l, 3]oxazolo[3, 2- a]pyrido[l, 2-d]pyrazine-8-carboxamide, sodium salt. |
|
With sodium hydroxide In ethanol; water at 20℃; for 0.5h; |
1 Reference Example 1: Experimental repetition of the final step of Example Z-9
Cabotegravir (278 mg, 0.66 mmol e.g. prepared according to the procedure disclosed in Example Z-9, which is referring to Example Z-l of WO 2006/116764 Al) was taken up in ethanol (10 mL) and treated with 1 N sodium hydroxide (aq) (0.66 mL, 0.66 mmol). The resulting suspension was stirred at room temperature for 30 minutes. Ether was added and the solid was collected by filtration. The obtained white solid was investigated by PXRD and found to be crystalline. Said crystalline material is designated Form A in the course of the present invention. |
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